Nicotinoylaminoethanesulfonylamino-thiazole and pharmaceutically acceptable acid addition salts thereof

ABSTRACT

AMINOETHANESULFONYL DERIVATIVES HAVING A GENERAL FORMULA R-SO2CH2CH2Y WHERE R IS SELECTED FROM A GROUP CONSISTING OF THIAZOLYL-2-AMINO, 1-PYRROLYL, 4-METHYLPIPERAZYL, AND 1-INDOLYL AND Y IS NH2 OR, WHEN R IS THIAZOLYL2-AMINO, SAID Y MAY BE NICOTINOYLAMINO AS WELL AS MANUFACTURE METHODS THEREOF WERE DISCLOSED.

United States Patent 3,743,647 NICOTINOYLAMINOETHANESULFONYLAMINO- THIAZOLE AND PHARMACEUTICALLY AC- CEPTABLE ACID ADDITION SALTS THEREOF Shun-Ichi Naito, 35 Murasakino Karnitoridacho, Kita-ku, Kyoto, Japan No Drawing. Filed July 19, 1971, Ser. No. 164,007 Claims priority, application Japan, Aug. 27, 1970, 45/75,350, 45/75,351, 45/75,352; Dec. 18, 1970, 45/ 114,446, 45/114,447

Int. Cl. C07d 31/48 US. Cl. 260294.8 D

2 Claims ABSTRACT OF THE DISCLOSURE Aminoethanesulfonyl derivatives having a general formula R-SO CH CH Y where R is selected from a group consisting of thiazolyl-Z-amino, l-pyrrolyl, 4-methylpiperazyl, and l-indolyl and Y is NH or, when R is thiazolyl- Z-amino, said Y may be nicotinoylamino as well as manufacture methods thereof were disclosed.

The present invention relates to aminoethanesulfonyl derivatives of the general formula in which R is selected from a group consisting of [El-Na and Y is NH In case R is thiazolyl-Z-amino, the Y may also be nicotinoylamino. This invention also relates to manufacturing methods for these aminoethanesulfonyl derivatives.

All of these aminoethanesulfonyl derivatives are novel compounds having never been disclosed in any liturature including patent specification. They are useful as medicines, such as analgesics, with little side effects. These compounds are characterized by containing taurine which is one of amino acids and has surface activity as well as analgesic action and, when they are given to human beings, their elfects are not lowered even when subjected to a detoxication reaction in vivo such as an acetylation. Furthermore, some of these compounds are also useful as anti-histaminic, hypocholesterolemic and anti-inflammatory drugs.

Although the compounds of this invention have considerable water solubility, they are resistant to moisture to such an extent that, even when they are allowed to stand in an open container placed in a room for one year, more than 90% of the content remains unchanged in most cases indicating little absorption of moisture. In addition, the aqueous solution thereof is also stable. Thus, for example, when a 5% aqueous solution of them is allowed to stand at room temperature for one year, more than 9095% thereof remains unchanged. This is practically advantageous, particularly in view of use of the compounds in injection.

Compounds of this invention can be manufactured by various routes which will be explained in detail.

Thus, for example, compounds where Y is nicotinoylamino group can be manufactured by nicotinoylation of the corresponding amino compounds or by nicotinoylamination of the corresponding halides. The latter method (nicotinoylamination of halides) will be disclosed later in an item of amination reaction.

The former method, i.e. nicotinoylation of aminoethanesulfonylaminothiazole (I), may be represented as:

In order to carry out the present nicotinoylation, any of known method for nicotinoylation may be employed. It is preferred to effect the nicotinoylation by use of acids bearing a nicotinoyl group or the functional derivatives thereof such as acid anhydrides, acid esters, acid halides or the mixtures thereof. These acids and their functional derivatives may also be employed in the form of their salts. The reaction may be carried out at either normal temperature or with heating and under normal pressures or pressures above normal, depending upon the kinds, quantities or the like of the reactants used. Furthermore the starting material (I) of the present reaction may be employed in its salt form.

The present method will be further explained in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method used only to illus trate but not limit the invention.

EXAMPLE 1 Into 0.1 mole of the starting material or its hydrochloride is added from 100 to 200 ml. of anhydrous pyridine with subsequent addition of nicotinic acid chloride hydrochloride (0.1 mol). After heating the mixture for an hour, or, alternatively, standing the same whole day at a room temperature, the mixture is heated for an additional one hour. The pyridine is distilled ofi? under reduced pressure from the reaction mixture, the residue recrystallized several times from either methanol or from ethanol to obtain the desired product (II) as its hydrochloride having a melting point of 289 C. (colorless needles). Into said residue from which the pyridine has been distilled off is added water and the mixture is made alkaline (pH about 9) by use of aqueous ammonia (of about 28%). The resulting mixture is evaporated under reduced pressure to dryness and the residue recrystallized several times from water to obtain the desired product (II) as colorless needles having a melting point of 228 C. The yields of the desired product and its hydrochloride are almost identical and within the range of from about to of the theory.

Element analysis Desired product (II):

Calculated for C H N O S (percent): C, 42.31; H, 3.85; N, 17.95. Found (percent): C, 42.37; H, 3.90; N, 18.03.

The hydrochloride of the desired product (II):

Calculated for C H N O S Cl (percent): C, 34.29; H, 3.64; N, 14.55. Found (percent): C, 34.40; H, 3.51; N, 14.58.

Employment of nicotinic acid chloride in place of the nicotinic acid chloride hydrochloride did not cause any change in yields. Furthermore, it has been ascertained that the condensation reaction between the starting material (II) or the salt thereof, and nicotinic acid chloride can proceed also in water or various organic solvents, as well as in pyridine and that it also proceeds advantageously when a small quantity of pyridine or alkali is added into the water or various organic solvents.

For example, 0.1 mole of the starting material (I) or its hydrochloride is charged with 500 ml. of ethyl acetate, into which mixture 0.1 mole of nicotinic acid chloride hydrochloride is added followed by heating under reflux in water bath for 3 hours. After distilling off the ethyl acetate from the reaction mixture yellowish solids remain, which are then recrystallized from ethanol or methanol to obtain the hydrochloride of the desired product (II). Alternatively, said residual solids are dissolved in a small amount of Water, which solution is made alkaline by use of ammonia (pH about 9) and distilled under reduced pressure to remove the water. The residue is recrystallized from water to obtain the desired product (II) in its pure form. In this case, the yield was little different from that obtained in the case of employment of pyridine as solvent.

In addition, in the following Examples 2 and 3 are shown the embodiments of the invention wherein nicotinic acid anhydride and nicotinic acid are employed in place of nicotinic acid chloride (hydrochloride) used in Example 1.

EXAMPLE 2 Into a 100 ml. three-necked flask are placed 0.1 mole of the starting material (I), 0.1 mole of nicotinic acid anhydride and 100 ml. of anhydrous pyridine followed by heating the mixture on boiling water bath with agitation for 7 hours. The pyridine is distilled off under reduced pressure and to the residue is added strong aqueous ammonia (of about 28%), to make it alkaline, whereupon yellowish-white substance precipitates. The mixture is, as such, subjected to distillation under reduced pressure to remove the water, the residue recrystallized several times from water to obtain the desired product (II) in its pure form. The crystals, when subjected to mixed examination using the corresponding standard, show no lowering in their melting point. The yield is about 70%.

EXAMPLE 3 Into a three-necked flask with a water-separating tube attached thereto are charged 0.1 mole of the starting material (I), 0.1 mole of nicotinic acid and 400 ml. of p-cymene followed by heating with stirring at a temperature of from 180 to 190 C. for about 6 hours. The water formed is azeotropically distilled off. After cooling, the p-cymene is distilled off under reduced pressure, the residue being made alkaline (pH about 9) by use of strong aqueous ammonia followed by distilling off the water under reduced pressure. The residue is recrystallized several times from water to obtain the pure desired product (II). The product, When subjected to mixed examination using the corresponding standard material, show no lowering in its melting point. The yield is about 65%.

Referring now by way of precaution, the method according to the present invention can also be effected by proceeding the reaction in the presence of catalyst. Nicotinoylaminoethanesulfonylaminothiazole (11) contains, in

its structure, a pyridine ring of nicotinic acid and, since the nitrogen atom in said ring is basic, it may be, of course, optionall reacted with any organic or inorganic acid to form the corresponding acid addition salt. Subsequently, in order to purify the end product, there may be employed, as well as the hydrochloride, any organic salts as for example, its fumarate, flavianate or tartarate. For example, the end product (II) may be readily purified by forming its hydrochloride by either adding thereto concentrated hydrochloric acid followed by evaporation under reduced pressure to dryness or introducing gaseous HCl into a solution of the desired product (11) in methanol or ethanol, with subsequent recrystallization of the hydrochloride from methanol or ethanol.

The above disclosure is an explanation in detail of a method to manufacture nicotinoylamino compounds by nicotinoylation of the corresponding amino compounds.

Compounds of the present invention in which Y is an amino radical can be manufactured by the following two methods:

(1) Amination of the corresponding halides (2) Deacylation of the corresponding acylamino (or acylimino) compounds The amination according to (1) will be explained at first together with a nicotinoylamination of the corresponding halides for the sake of convenience.

Said amination method can be accomplished by the reaction of the halide of the formula (where R is as defined already; Z is halogen) with ammonia or nicotinic acid amide.

The halogen designated by Z in the above-described formula is preferably chlorine, bromine or iodine, of which chlorine is particularly preferred.

The ammonia or nicotinic acid amide to be reacted may be used as such or after dissolving or suspending in water and/or organic solvent, and its salts with acids may also be employed, if desired. The reaction in accordance with the present invention may proceed under normal pressure, although it is preferred to carry out the reaction under pressure above normal, in which case it is more preferred to effect the reaction in the presence of catalyst as for example, NaI, Cu Cl NH I or the like compound.

The halides to be employed as the starting materials according to the present invention are also novel compounds having been described in no literature and may be prepared, for example, by reacting Z-aminothiazole, N-methylpiperazine, pyrrole or indole with haloethylsulfonyl halide.

The present invention will be further described in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present invention and the invention be never limited thereto.

EXAMPLE 4 (Y=NH2) 10 g. of the compound of the Formula III wherein X is Cl is reacted in an autoclave in the presence of catalyst with either anhydrous ammonia or with ammonium carbonate and aqueous ammonia by heating the reactants. After completion of the reaction, the contents are made acidic by use of hydrochloric acid, the resulting precipitates removed by filtering off the same under suction, the filtrate evaporated under reduced pressure to dryness and the residue recrystallized from quantities of ethanol to obtain the hydrochloride of the desired product. Alternatively, the said filtrate is made alkaline by use of strong aqueous ammonia (to pH about 9) followed by evaporation under reduced pressure to dryness, the residue recrystallized from either water or from a mixture of water and acetone to obtain the desired product. The melting points and details of the reaction conditions are shown in Table 2, while the element analysis in Table 3.

TABLE 1 M P. of the hydrochlor- M.P. of the desired ide of the desired The desired product wherein R is thiazolyl-Z-amino and Y is nieotinoylamino) has a melting point of 229 C. and the hydrochloride thereof 288 C.

R product product The above is an explanation as to the manufacture of M.P. 345-352" (colored M.P.318319 (colored 5 delfed compounds by amillafion HiCOtiIIOYI- CHE-N g g g egggpg gag gs g g g amlnation) of the corresponding halides.

ry As hereunder is an explanation of deacylation of the (Ia) corresponding acylamino (or acylimino). compounds. M.P.d352a356 (calorie? M26319??? M01? particularly, said method is concerned with a procan ecompose an ecompose e S colorless crystals colorless crystals 10 s or preparing the desired products by deacylating, by

way of hydrolysis of hydrazrnolysis, a compounds rep- (Ib) resented by the general formula 'N M.P.d325(-1332(co1or;)d M.P. taiid", colorless an 60011111059 OI'YS I colorless crystals. 2 Z 2Q NH-- 15 s (Id) wherein R represents the same meanings as described above and Q 1s an acylamino or acylimino group. Pre- M.P.323-328 (colored M.P. 258-264" (colored rred and decomposed. and decomposed) fe examples of the acylamino group mclude aliphatic acylammo groups such as acetylamlno and PIOPlOlJYlammo groups, as well as aromatic amino groups such as N benzoylarrnno and mcotinoylamino groups. Preferred ex- (I8) ample of the acylnmno group is phthalimino group. Of

course, these specific examples of the acylamino and acyl- TABLE 2 Catalyst and Temper- Yield (percent) the added Reaction ature amount Startingamine (g.) time (hrs.) C) Ia Ib Id Ie thereof (g.)

n d oni 20 s 100 50 43 36 4o NaI(0.45). An 5 100 52 45 4o 48 011101? 1.0

00 10 28 NH OH iiomif 4 s 140 s 34 as 011.01. (0.4

Nora-When the above-desired reaction was repeated except that there was employed, as

the starting materiar,

the bromide (X=Br) or iodide (X=I) in place of the chloride (X=Cl) there resulted some reaction in yields. Similar reducu'on in yields occurred also when using no catalysts.

EXAMPLE 5 (Y==NICOTINOY'LAMINO) (C) To 5 g. of the compound of the formula (II) wherein R is thiazolyl and Z is Cl is added 8 g. of nicotinic acid amide or its hydrochloride, and the mixture is reacted, in an autoclave, in the presence of 3 g. of Cu Cl at a temperature of 100 C. for about 6 hours. The contents are thereafter made acidic by use of hydrochloric acid, the precipitates formed thereby filtered off under sunction. The filtrate is evaporated under reduced pressure to dryness, the residue recrystallized from methanol or ethanol to obtain the hydrochloride of the desired product (i.e. nicotinoylaminoethanesulfonylaminothiazole hydrochloride).

Alternatively, the filtrate as described above is made alkaline by use of ammonia and evaporated under reduced pressure to dryness, the residue being recrystallized from water to obtain the desired product as colorless needles. Yield about 20%. Its molecular weight and element analysis are shown in Table 3. As in Example 4, there resulted some reduction in yield when there was employed, as the starting material, the bromide (Z=Br) or iodide (Z=I) or no catalysts were employed.

imino groups are mentioned only by way of example to explain the present invention. Therefore it will be understood that the present invention be by no means restricted to employment of such specific examples.

The above-described hydrolysis may be effected advantageously in any known manner where there are employed, for example, acids, sodium alcoholate, alkali metal hydroxides, alkali metal carbonates or the like materials. In particular, preferred results may be obtained in the present invention when a concentrated solution of alkali metal hydroxide such as NaOH or KOH.

When the deacylation of the invention is to be elfected by hydrazinolysis, there may be employed any known method for it, such as one wherein hydrazine hydrate is added into a methanolic or ethanolic solution with subsequent treatment with hydrochloric acid.

Starting materials in this method are also novel compounds having never been described in any literature and may be prepared, for example, by the reaction of N- methylpiperazine, pyrrole, indole or Z-aminothiazole with an acylaminoethanesulfonyl halide.

TABLE 3 Percent Calculated Found Molecular Compounds formulas G H N C H N Ia(N-methylpiperazine family) C H 1N 0;S 40.58 8.21 20.29 40.65 8.18 20.20 Ia (hydrochloride) (N-methylpiperaz eiamily) C1HzoN OzSCl; 26.50 6.31 13.25 26.72 6.28 13.33 Ib(gyrr0le family) CflHmNaO 41.38 5.74 16.09 41.25 5.82 16.21 Ib( ydrochloride)(pyrroleiamly) CeHnNzOaSCh 29.15 4.87 11.34 29.28 4.76 11.42 Ie(thiazoleia mily) 0 11511 1140 8, 42.31 3.85 17.95 42.38 3.91 17.72 10 (hydrochloride) (thlazoleiamlly)- C1 H14N4O SzCh 34.29 3.64 14.55 34.31 3.60 14.47 Id (thiazoleiamily) C5HQN3O2S: 28.99 4.35 20.29 29.12 4.21 20.34 Id (hydrochloride) (thiazole iarmly)- csnnNamszoi, 21.43 3.93 15.00 21.38 3.99 15.23 Ie(1ndolylfamliy) C H NgmS 53.57 5.36 12.50 53.63 5.28 12.63 Ie (hydrochloride) (i ndolylfamily) CmHmNgOQSCl 46.07 4.99 10.75 46.11 4.89 10.68

7 The present method will be further illustrated in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method and the present invention be never limited thereto.

Table 5. The element analysis of the desired products thus obtained are shown in Table 6.

All of the resulting products are in the form of colorless crystals.

TABLE 5 E Amount Yield EXAMPL 6 R Q used (g.) (8-) Into the starting material wherein Q is phthalimino Phthallrnino 10 4.5 group is added a 30 W./v. percent solution of hydroxid 1O CH N Acetammo 10 followed by boiling the mixture under reflux for 3-5 Phh H hours. After cooling the mixture is made acidic by use 1{ j;;;;;;;; 13 2:3 of concentrated hydrochloric acid while ice-cooling, and a then adjusted to a pH of about 9 by addition of sodium Phthaummo 10 carbonate. The crystals precipitated thereby are sepa- 15 Acetamino 10 6.2 rately stored. The filtrate is evaporated under reduced I pressure to dryness, the residue being recrystallized from \N either water or from a mixture of water and acetone and the resulting crystals, together with the prev1ously Phthaumjno 10 32 stored crystals, being recrystallized several times from Acetamino 10 3.5 either water or from a mixture of water and acetone to J| obtain the desired product as colorless crystals. The de- 5 tails of these reactions are shown in Table 4.

TABLE 0 Percent Calculated Found Molecular R formula C H N C H N o H N o 8 40.58 8.21 20.29 40.67 8.18 20.33 HaC-N N 7 l7 3 3 q o ioNzozS 41.38 5.74 16.09 41. 5.83 16.22

CIOHIZNHOQS 53.57 5.36 12.50 53.68 5.38 12.60

N CsHoNaOzS: 28.99 4.35 20.29 29. 05 4.30 20.38

TABLE 4 EXAMPLE 6 g f fi To the starting material wherein Q is phthalimino hydioiide MP fth Y1 1d group is added from about 5 to 8 times its volume of u on .0 e R (10 g.) jg (11111.) desired product 6 95% ethanol followed by the addition of 1.1 times its 0 molar amount of hydrazine hydrate (of about 100%). HQO-N N- 50 o lo iiioifipoiikf e mixture is heated under reflux for about 2 hours with continuous stirring. Thereafter, the mixture 1s ad- 50 M P 35 35 o( d a0 justed to a pH of about 1 by the addition of hydro N- and decomposed). chloric acid, heated on water bath for about a further 30 minutes and filtered in hot to remove the precipitated 4o M.P.323330 (colored 3.5 phthalic acid hydrazide, the filtrate being cooled to predecomposed) cipitate the hydrochloride of the desired product which is then filtered and then recrystallized several times to purify the same. [Alternatively, the said filtrate is evapo- 1 rated under reduced pressure to dryness and the residue N 40 25 3 o Z3 iS made alkaline about by th? addition Of a I and decomposed)- Na C0 solutlon followed by evaporating again under reduced pressure to drwiess. The residue is recrystallized 8 several times from water or from a mixture of water and acetone to obtain the free desired product.] The Similar procedures are repeated except that there are details of the reactions are shown in Table 7. In addition, employed, as the starting material, ones wherein Q is the element analysis of the hydrochloride of the desired benzoylamino or acetylamino group, the corresponding 7 product is shown in Table 8.

desired products are obtained in yields as tabulated in By the way, when, in Example 6, sodium carbonate is employed to make the reaction mixture alkaline, the hytained by reducing the amount thereof added and theredrochloride as obtained in this example may be also obby making the mixture weakly acidic.

TABLE 7 Amount ot Solvent used Starting for recrystalmatenal Hydrazine M.P.ofthe HClsaltofthe desired Yiel liziug the R used (g.) hydrate (g.) product (g.) H01 salt 130 22 M1. SIS-319 (colored and de- 52 Ethanol. GHQ-N N- composed).

=\ 122 22 Ml. (HQ-322 (colored and de- 45 Do.

composed).

:m'..:..'.;:;:...::.;. M.P. 258-264? (colored and de- Do. |J composed).

"N M.]?. 325-332 (colored and de- Methanol."

composed).

NH S TABLE 8 Percent Calculated Found R Molecular formula C. H N C H N ovmomozs 01 26.50 6.31 13.25 26.43 6.45 13.38 CHs-N N- \N CHIINaOaSCl 29.15 4.87 11.34 29.27 4.78 11.45

What is claimed is:

What is claimed is: 1. A compound of the formula:

NH-S 0,oH,oH,Y

wherein Y is nicotinoylamino, and the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1 s n-nu-so omonmnoo References Cited 'Postovskii et a1.: Chem. Abstracts, vol. 39, pp. 1151,

ALAN L. ROTMAN, Primary Examiner 

